65ª Reunião Anual da SBPC

C. Ciências Biológicas - 8. Genética - 3. Genética Humana e Médica

COMPARATIVE ANALYSIS OF EXPRESSION PATTERNS OF TWO GENES LINKED TO BRAIN CALCIFICATIONS (SLC20A2 AND PDGFRB) BASED ON THE ALLEN INSTITUTE HUMAN BRAIN ATLAS

João Ricardo Mendes de Oliveira - Keizo Asami Laboratory - UFPE / Department of Neuropsychiatry - UFPE Isis Carla de Lima Pereira - Keizo Asami Laboratory - UFPE Regina Juliana Galdino da Silva - Keizo Asami Laboratory - UFPE / IFPE

INTRODUÇÃO:

Familial Idiopathic Basal Ganglia Calcification (FIBGC), also known as "Fahr's disease," is a neuropsychiatric disorder with motor and cognitive symptoms. It is characterized pathologically by bilateral calcification most commonly in Basal Ganglia, but also in other brain regions such as Thalamus and Cerebellum. Most affected families present an autosomal dominant pattern of inheritance, and FIBGC has been shown to be a genetically heterogeneous disease. Wang et al. (2012) reported various families from China, Spain and Brazil carrying mutations in the SLC20A2 gene, the first to be linked to this condition. This gene encodes for the inorganic phosphate transporter PiT-2, which plays a role in Na+/Pi co-transport, serving a housekeeping function in Pi homeostasis. From the analysis of a large French family with autosomal dominant inheritance with no SLC20A2 mutation, Gaël et al. (2013) recently pointed PDGFRB as a new disease-causing gene for FIBGC. PDGFRβ is a cell-surface tyrosine kinase receptor for members of the platelet-derived growth factor family, and its activation can induce cellular proliferation, differentiation, survival and migration. SLC20A2 impairments correspond to majority of mutation findings in affected families.

OBJETIVO DO TRABALHO:

It is aimed to compare, by microarray data analysis, the expression patterns of SLC20A2 and PDGFRB in the regions most commonly affected in FIBGC. This comparative approach is adopted in order to further verify similarity and possible discrepancy between the expression profiles of these which are the only two genes identified to be linked to FIBGC until the moment.

MÉTODOS:

We used the Allen Institute Human Brain Atlas (AIHBA) resources, http://human.brain-map.org/, to study the expression pattern in the brain for SLC20A2 and PDGFRB. The AIHBA dataset contains microarrays data derived from four adult human brains from donors with no previous history of neuropsychiatric symptoms. We limited our analysis to the samples for which data of both hemispheres are presented. Hybridizations used for each gene of our interest two different probes. We performed our analysis only with the probes that correspond to fragments located in portions of coding sequence. The analysis focused in the structures commonly calcified in FIBGC patients: Basal Ganglia, Thalamus and Cerebellum. We conducted an evaluation of gene expression by using a measurement of expressivity associated to anatomical structure. This expression measure was available in format normalized according to microarray technical used for AIHBA. An average expression level was attributed to each chosen brain regions for each gene, thus allowing comparison and making possible draw conclusions.

RESULTADOS E DISCUSSÃO:

The microarray data analysis revealed that the neuroanatomical expression profiles for SLC20A2 and PDGFRB exhibit either points of similarity and opposition. The regions highlighted with similarity correspond to structures where both genes present high or low levels, relatively to each gene own average of expression intensity in the brain. An opposite pattern means that while one of the genes is high expressed in that specific region, the other is low expressed. This might help to explain why so far more than twenty FIBGC families were linked to mutations in SLC20A2 and only two were linked to PDGFRB.

CONCLUSÕES:

In this analysis, we provide comparative assessment about gene expression patterns in the neuroanatomical regions that are most frequently calcified in FIBGC of SLC20A2 and PDGFRB, shown to be involved in this disease. The finding that these two genes have similar relative high expression levels in some regions supports the hypothesis that both PiT-2 and PDGFRβ proteins influences in the progression of FIBGC. We encountered, however, significant expression heterogeneity amongst samples and structures. Analysis with a larger set of samples from the AIHBA, which is an ongoing process, will be necessary to fully explain the impact of the gene expression pattern for SLC20A2 and PDGFRB in the brain and why this confer a heterogeneous vulnerability to FIBGC.

Palavras-chave: Basal ganglia calcification, Fahr’s disease, Microarray.